Despite numerous clinical trials, no medication has been approved to treat methamphetamine (MA) dependence. Dysfunction in dopaminergic systems and cognitive dysfunction al'e hallmarks of stimulant dependence and predict poor response to behavioral treatment for cocaine and MA dependence. As a result, novel approaches to restoring dopaminergic functioning is a promising approach to developing medications for MA dependence. Ibudiiast (IBUD) is a phosphodiesterase inhibitor and modulator of glial cell activation that may be effective for MA dependence via reductions in neuroinflammation and/or induction of neurotrophic factors such as GDNF. In preclinical studies, IBUD reduced MA-prime- and stress-induced reinstatement of MA seeking in rats, suggesting IBUD is a promising candidate medication with potential effects in restoring dopaminergic functioning. The proposed study is a phase II randomized, double-blind, clinical trial of IBUD (N=60) versus placebo. (N=60) with cognitive behavioral therapy for 12 weeks to detenmine the safety and efficacy of IBUD for MA dependence. Primary aims will compare MA use and treatment retention for IBUD versus placebo. The study has >80% power to detect a benefit for IBUD over placebo on the FDA-preferred outcome in stimulant trials: urine drug screen confirmed MA abstinence during the final two weeks of treatment (yveeks 11/12). Effects of potential confounders including medication safety/tolerability, medication non-adherence, and ability to achieve MA abstinence with a contingency management intervention during a two-week trial lead-in period, on outcomes will be assessed. Potential mechanisms of IBUD in MA dependence will be probed in exploratory analyses examining any effects of IBUD on cognitive function and changes in cognition during treatment, and associations between treatment outcomes and polymorphisms in dopaminergic genes, the gene for GDNF, and serum GDNF levels. A phase I human safety-interaction study of IBUD in MA dependence is currently undenway at our Center and will be completed prior to funding of this proposed study. The proposed trial is the result of a long-standing , collaboration between our research Center and MediciNova, Inc. who are fully committed to seeing IBUD through the regulatory and marketing process for MA dependence. If unanticipated events preclude advancing IBUD into phase II testing in time for this study, the bupropion-naltrexone combination formulation undergoing phase 1 testing in Project 1 of this proposal will be advanced to phase II testing instead. RELEVANCE (See Instructions): Methamphetamine dependence is a significant source of detrimental consequences to individual and public health including psychiatric distress (paranoia, suicidality, etc.), neurologic effects (neurological impairment, stroke, seizures), HIV and hepatitis C infection, and cardiovascular disease. Identification of an effective pharmacotherapy for MA dependence would have a significant public health impact.